ABSTRACT: Psoriasis is a debilitating auto-immune disease that affects 125 million people worldwide. While some patients can be treated successfully with existing non-specific therapies, there is a dire need for developing new targeted treatments that are durable and have on side effects. T cells in the skin that secrete inflammatory cytokines promote chronic lesions. Studies by our lab and others have shown that these inflammatory T cell responses are programmed by dendritic cells (DCs). The skin DC system is intricate and is comprised of distinct subsets, each with unique receptors for inducing either immune responses or immune tolerance. Extensive understanding of the type of DC and the unique signals that promote inflammatory T cell responses in psoriasis is a gap that remains and essential for designing much needed relief for patients. This application focuses on our recent discovery of a new human DC subset in skin that is delineated by CD5 expression. The CD5+ DC inhabit both the epidermis and the dermis of healthy human skin and are superior in their capacity to activate effectors and inflammatory TH cell responses (including CTLs, TH1, TH17 and TH22). Moreover, these DCs are significantly more plentiful in psoriatic inflamed skin, which suggests they are critical players in pathogenesis. Consistent with this notion, new preliminary data are provided to demonstrate that CD5 functions to trigger an inflammatory pathway of DC maturation and inflammatory T cell activation. CD5-deficient DCs produce less inflammatory cytokines upon activation, and activates T cells less efficiently than WT DCs. Moreover, CD5-/- mice display reduced pathology in a mouse model of psoriasis. These results mandate further investigation of the impact of CD5-expressing DCs on skin immunity and their potential exploration for psoriasis therapy. Our central hypothesis is that: CD5 represents a novel immune-stimulatory molecule on DCs, and that alterations to the proportions or functions of CD5+ DCs contribute significantly to autoimmunity. To test this, in Aim 1 we propose experiments to determine the mechanisms by which CD5 on DCs facilitates activation and antigen uptake to initiate T cell immunity; Aim 2 will determine whether CD5 drives T cell?mediated inflammation in psoriatic skin by using a new mouse that we developed that lack CD5 specifically on DCs; and in aim 3 we will define the anatomic distributions of CD5+ DCs in skin of psoriatic patients, physical interactions with immune cells and activation of autoreactive T cells. It is anticipated that these studies will lead to new fundamental insights into immune regulation by CD5- expressing DCs and will have direct impact on strategies to target and deactivate DCs, leading to safe and effective applications for psoriasis and other inflammatory diseases in and beyond the skin.